In the United States and most other developed countries, the leading cause of mortality and morbidity is cardiovascular disease. Deaths from cardiovascular disease outnumber those from cancer by a factor of nearly two to one. Of those patients with cardiovascular-related diseases, coronary disease is the most important.
The heart, like any other tissue, requires a constant supply of blood in order to function properly. The blood supply to the heart is delivered through the coronary arteries. Patients with coronary artery disease usually have narrowings in one or several of these arteries. As a result, blood supply to the heart muscle is impaired. These narrowings are usually caused by deposits of fat, cholesterol, clotted blood and arterial tissue that calcify and harden over time (arteriosclerosis). If the supply of blood to the heart muscle is diminished below a certain level, then the heart muscle may initiate a series of responses that cause chest pain (angina). If the blood supply to an area of heart muscle is completely interrupted for a period of hours, then that area heart muscle will die (myocardial infarction or "heart attack").
Over the past several decades important developments have decreased the mortality and the suffering of millions of patients with coronary disease. The development of coronary artery bypass graft surgery (CABG) has proved to be useful in decreasing the incidence of coronary-related chest pain and, in selected cases, prolonging survival. In the late 1970's another method of mechanically increasing blood flow to the heart was developed. This technique is known as percutaneous transluminal coronary angioplasty (PTCA). A PTCA procedure is performed by placement of a catheter into an artery in the arm or leg. The catheter is then advanced to the coronary artery. A smaller catheter with a balloon near its tip is then advanced through the guide catheter and into the coronary artery. The angioplasty catheter is then placed into the obstruction and inflated. The pressure from the balloon is transmitted to the obstruction. This causes the artery to stretch and its inner lining to tear at the site. In addition, the narrowing is compressed against the artery wall. The balloon is then deflated and both catheters are removed. After allowing a period for the entry site in the arm or leg to heal (6-12 hours), the patient usually begins ambulating and may return to work after several days.
Although successful PTCA procedures produce a significant decrease in angina in selected patients, there are two major complications associated with this procedure: (1) acute occlusion of the vessel during or soon after the procedure, and (2) a process known as restenosis, where the vessel gradually narrows at the site of the PTCA.
The occurrence of acute occlusion at the angioplasty site is a serious complication and is the major contributor to the mortality and morbidity associated with PTCA. Acute occlusion of the vessel during or immediately after PTCA increases the procedure-related mortality five-fold when compared to occlusion-free patients. The myocardial infarction rates associated with acute occlusion are also significantly higher than in occlusion-free patients (27-56% versus 2%, respectively). Because of these complications, patients who experience an acute occlusion during an angioplasty procedure may undergo emergent coronary artery bypass grafting to restore myocardial blood flow. As expected, the mortality and incidence of myocardial infarction in patients who undergo emergent bypass grafting for acute closure are significantly higher than those of occlusion-free patients. Despite the experience gained since the early application of coronary angioplasty and improvements in catheter technology, the incidence of periprocedural acute closure has not changed in the period between two multicenter registry trials completed in 1981 and 1986. In addition, there has not been a significant change in the complications associated with acute closure.
Several studies have examined the coronary arteries of patients who died within several days of PTCA. These studies demonstrated that disruption and splitting of the atherosclerotic plaque, in addition to expansion of the vessel wall (particularly by the segment uninvolved by atherosclerosis) were the most likely causes for the improved angiographic appearance of the vessel. The investigators consistently found cracks and dissections between the intimal and medial layers at the junction of the plaque and the plaque-free segment of the arterial wall. These findings suggested that an uneven distribution of force existed between a rigid and somewhat non-expansile arteriosclerotic plaque and a more compliant less-arteriosclerotic area of the vessel wall. It was suggested that the lateral forces of the balloon induced tears at the junction of the two unequally elastic segments. These studies confirmed that the mechanism of PTCA was not due to compression and redistribution of the plaque but rather to extensive injury to the less arteriosclerotic segments of the artery. Variable degrees of intimal and medial plaque disruption occur during all PTCA procedures. Some lesions may demonstrate only mild, superficial splitting while others may display gross fissuring through the entire media and plaque mass, resulting in tears or dissections of the inner layers of the artery.
Although the exact cause of acute closure is unknown, the presence of large intimal tears or arterial dissections after PTCA has been consistently identified as a predictor of major ischemic complications. Although the angiographic detection of intimal disruption is somewhat insensitive, several studies have associated these tears and dissection with immediate vessel closure during PTCA. A reasonable assumption is that the intimal tears and dissections either directly occlude the artery or markedly disturb the flow patterns in the vessel and allow areas of blood stasis to form. Since non-flowing blood is very likely to clot, thrombus formation could begin in these areas of stasis and the thrombus may continue to grow until the vessel occludes.
Because of the serious complications associated with acute closure, several devices have been developed for use in this situation (Roubin et al., Circulation 81:92-100 (1990); Jenkins et al., Circulation 82:101-108 (1990); Stack et al., Amer. J. Cardiol. 61:77-80 (1988)). The device that appears to be most useful is the intracoronary stent. A stent is a device (usually made of metal) that can be placed in the artery at the site of the dissection. The use of intracoronary stents for the treatment of acute closure has markedly decreased the incidence of associated myocardial infarction and emergent coronary bypass surgery (Roubin et al., Circulation 83:916-927 (1992)). The proposed mechanism of action of intracoronary stents in the treatment of acute closure is the pinning of the intimal tears between the stent and the arterial wall, thereby maintaining vessel patency.
Although stents have been shown to be very effective in restoring vessel patency and decreasing myocardial ischemia, the exposure of the metal prosthetic surfaces to circulating blood initiates platelet and coagulation reactions that frequently result in thrombus formation and acute thrombotic occlusion of the stent. The occurrence of thrombosis at the stent site is a life-threatening emergency that usually results in an emergent coronary angioplasty or emergent coronary bypass surgery.
Because it is of utmost importance to avoid thrombosis of the stent and its serious complications, patients who receive stents are aggressively anticoagulated with heparin, aspirin, coumadin, dextran, and persantine. As expected, there is a high incidence of bleeding complications in these patients. A study performed at Emory University Hospital revealed that 33% of the patients who received stents for acute closure required transfusion and 7% of patients had an extremely large bleeding episode at the catheter entry site in the leg artery that necessitated surgical repair (Hearn et al., "Clinical and angiographic outcomes after coronary artery stenting for acute closure following percutaneous transluminal coronary angioplasty: initial results with a balloon-expandable, stainless steel design,"J. Am. Coll. Cardiol. (in press) (1992).
Because of the complications associated with systemic anticoagulation, extensive attempts have been made to design a stent that would be non-thrombogenic. A stent with little or no propensity to form thrombus would obviate or drastically decrease the need for aggressive anticoagulation. Initial stents were constructed of plastic. Because all of these stents thrombosed, stainless steel was then used. These stents appeared promising in canine peripheral arteries; however, most coronary stents used in clinical trials are composed of stainless steel and have a thrombotic occlusion rate of approximately 5-30%. Tantalum is another metal that is used in first-generation stents. Althrough initial reports of a lower thrombogenicity of tantalum stents appeared promising (van der Giessen et al., Circulation 80:II-173 (1989)), more careful study has shown that tantalum is as thrombogenic as stainless steel (de Jaegere et al., Amer. J. Cardiol. 69:598-602 (1992)).
The concept of coating a stent with a polymer has been described several years ago and is discussed in the literature regularly. In the past, local delivery of drug(s) using stents has centered around two concepts: (1) directly coating the stent wires with a drug or a drug-polymer combination (Bailey et al., Circulation 82:III-541 (1990); Cavendar et al., Circulation 82:III-541 (1990)) and (2) incorporating a drug into a stent that was constructed not of metal but of a biodegradable polymer (Murphy et al., J. Invasive Cardiol. 3:144-148 (1991)). Most investigators and stent companies have focused their efforts on directly coating the metal stent wires with a polymer. This polymer is usually placed directly on the stent (e.g., by dipping the stent in soluble polymer) or is covalently bound to the metal. The polymer is bonded to or contains an anticoagulant compound. Most coated stents currently under development use heparin as their active agent. One of the more effective polymer coatings for stents is Biogold (van der Giessen et al., Circulation 82: III-542 (1990)).
Unfortunately, Biogold and other coated stents have not completely prevented arterial thrombosis. This is probably related to the cracking of the polymer as the stent is expanded during deployment, saturation of the anticoagulant binding sites on the stent, and/or inadequacy of heparin as an anticoagulant in the prevention of arterial thrombosis.
Because of the inadequacies associated with polymer coatings directly applied onto the stent wires, there remains a great need to effectively prevent thrombosis at the stent site. The present invention satisfies this need by providing a separate sleeve to encompass the stent and serve as a local drug delivery device to prevent thrombosis.
In addition to thrombosis, restenosis is also a problem associated with angioplasty. Repeat coronary angiography usually reveals a significant stenosis at the PTCA site (i.e., restenosis). Usually these patients are left with a choice of repeat PTCA or coronary artery bypass surgery. There are approximately 300,000 coronary angioplasty procedures performed in this country annually. Since 30% of these procedures are complicated by restenosis, the development of an effective method to treat this problem would have an enormous impact on health care costs and the morbidity associated with PTCA.
In an attempt to prevent restenosis after PTCA, a large number of pharmacologic agents have been employed in clinical trials. Therapy with heparin, aspirin, coumadin, calcium channel blockers, thromboxane receptor antagonists, steroids, omega-3 fatty acids, and angiotensin converting enzyme inhibitors have failed to unequivocally prevent restenosis.
A porcine coronary balloon injury model has been developed in an attempt to find an animal model more representative of human post-angioplasty restenosis (Schwartz et al., Circulation 82:2190-2200 (1990); Karas et al, "Comparison of coronary intimal proliferation following balloon injury and stenting in swine: An animal model of restenosis," J. Am. Coll. Cardiol. (in press) (1992)). Morphologically and hemodynamically the porcine coronary vasculature is very similar to the human coronary system. Reproducible intimal proliferation is obtained after balloon injury of normal porcine coronary arteries. Histologically, the proliferative response to balloon injury in the pig coronary is very similar to the response seen in pathological studies of humans (Schwartz et al., Circulation 82:2190-2200 (1990)).
Thus, there is also a need to prevent restenosis following angioplasty. The present invention satisfies this need by providing a separate sleeve to encompass a stent to locally administer drugs to prevent restenosis.